Failure of iron chelators to reduce tumor growth in human neuroblastoma xenografts.
Neuroblastoma (NB) is a high risk tumor of childhood, and raised serum ferritin is an adverse prognostic factor. The hypothesis that iron chelation therapy impacts tumor status and patient prognosis through changes in iron metabolism has been systematically evaluated here in a xenograft model of human NB. One of two iron chelators was given in seven different regimens to nude mice xenografted s.c. with either IMR-32, an established cell line, or JBN-1, heterotransplanted directly from a patient. Nude mice (a total of 160 in 24 cohorts) were given: desferrioxamine (DFO) by s.c. bolus or reservoir; 1,2-dimethyl-3-hydroxypyridin-4-one (L1), i.p. or orally; or saline. Measurements of mean Hb and liver iron levels were compared with corresponding saline cohorts per regimen as well as for pooled cohorts per agent for both cell lines. For IMR-32 xenografts, significant differences in Hb were achieved with L1 (10.9 g/dl pooled versus 13.7 g/dl controls) and in liver iron with DFO and L1 (235 microg/g and 306 microg/g, respectively, versus 520 microg/g). For JBN-1, the pattern was similar. With L1, H6 was 10.2 g/dl and controls were 11.7 g/dl (individual DFO cohorts were also significant); liver iron with DFO was 303 microg/g, liver iron with L1 was 270 microg/g, and controls were 387 microg/g. Additional therapy prior to tumor injection (67 mice and 10 cohorts) did not increase the depletion. Despite documentation of iron depletion, no reductions in tumor engraftment, latency, or tumor size at end point were achieved in the chelator-treated mice, compared with controls populations. Accordingly, inclusion of these iron chelators in clinical trials for NB appears unwarranted.
Selig
R A
RA
Childrens Cancer Research Institute, Sydney Children's Hospital, Randwick, NSW, Australia.
White
L
L
Gramacho
C
C
Sterling-Levis
K
K
Fraser
I W
IW
Naidoo
D
D
D000284:Administration, Oral; D000818:Animals; D002675:Child, Preschool; D000077543:Deferiprone; D003676:Deferoxamine / Q000008:administration & dosage / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005293:Ferritins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011728:Pyridones / Q000008:administration & dosage / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D006454:Hemoglobins; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine